Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oligodendrocyte progenitors are highly susceptible to oxidative stress due to their limited content of antioxidants and high iron levels. We previously showed that iron plays a central role in the toxicity of dopamine (DA) to oligodendrocyte progenitors. Here, we further explore the mechanisms involved in DA toxicity, specifically the role of superoxide and the glutathione system. DA induces accumulation of superoxide, membrane damage and loss in cell viability. An iron chelator, deferoxamine, reduces superoxide accumulation. However, a superoxide dismutase mimetic, MnTBAP, potentiates DA toxicity, suggesting that superoxide plays an indirect role in toxicity through dismutation to H2O2. In addition, the glutathione (GSH) analog (GME), blocks DA-induced superoxide accumulation, heme-oxygenase-1 (HO-1) expression and caspase-3 activation, and reduces cell death, while the glutathione synthetase inhibitor, buthionine sulfoximine, potentiates DA-induced HO-1 expression and cell death. Moreover, a mimetic of the peroxide-scavenging enzyme, glutathione peroxidase (GPx), ebselen, blocks caspase-3 activation induced by DA alone or in combination with iron. In conclusion, superoxide and inadequate defense by glutathione and GPx are responsible for the susceptibility of oligodendrocyte progenitors to DA toxicity. Furthermore, peroxides play a primary role in toxicity induced by DA and iron.
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PMID:Deficient peroxide detoxification underlies the susceptibility of oligodendrocyte progenitors to dopamine toxicity. 1740 Feb 58

Recent studies indicate that iron (Fe) is involved in neurotoxicity caused by inorganic lead (Pb). We studied the role of Fe in the effects Pb-induced cerebral apoptosis during rat development and to explore its possible regulatory mechanism. In the present study, weanling male Sprague-Dawley rats were randomly divided into four groups. Three groups of rats received 400 microg/mL Pb acetate solution in drinking water, among which two of the groups were concurrently given 20mg/kg and 40mg/kg FeSO(4) solution, respectively, as the low and high Fe group, for 6 weeks. The Fe doses were administered orally by gavage every other day according to animal body weight. For the control group, Na acetate with an acetate concentration equivalent to the high dose of Pb acetate was prepared in the same manner. At the end of the study, exposure to Pb in drinking water significantly promoted internucleosomal DNA fragmentation, enhanced the percentage of TUNEL-positive cells and increased the caspase-3 activities in cortex as compared to the controls. At the same time, it did cause a significant decrease in cortex Fe concentrations. Concomitant supplement with different dose Fe appeared to restore brain Fe level to the normal level. Although the low dose of Fe restored brain Pb level to the normal level and the high dose of Fe did not, both of them reduced the formation of DNA fragments, showed few TUNEL-positive cells with yellow nuclei and inhibited Pb-induced procaspase-3 degradation. Western blot showed that exposure to Pb caused a significant elevation in the phosphorylation of ERK1/2, JNK1/2, and Elk-1. Low Fe supplemental treatment suppressed the phosphorylation of ERK1/2 and JNK1/2 but not Elk-1. Interestingly, high Fe treatment slightly suppressed the phosphorylation of JNK1/2, but significantly elevated the phosphorylation of ERK1/2 and Elk-1. Collectively, the current study suggests that supplementation of Fe during Pb treatment prevents against cytotoxicity and apoptosis induced by Pb insults, in which MAPK pathways play an important role in Pb-induced cerebral apoptosis by activating the MEK-ERK pathway that suppresses JNK signaling.
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PMID:Iron supplementation protects against lead-induced apoptosis through MAPK pathway in weanling rat cortex. 1756 Jun 53

Accumulation of iron at sites where neurons degenerate in Parkinson's disease (PD) and Alzheimer's disease (AD) is thought to have a major role in oxidative stress induced process of neurodegeneration. The novel non-toxic lipophilic brain- permeable iron chelators, VK-28 (5- [4- (2- hydroxyethyl) piperazine-1-ylmethyl]- quinoline- 8- ol) and its multi-functional derivative, M-30 (5-[N-methyl-N-propargylaminomethyl]-8-hydroxyquinoline), as well as the main polyphenol constituent of green tea (-)-epigallocatechin-3-gallate (EGCG), which possesses iron metal chelating, radical scavenging and neuroprotective properties, offer potential therapeutic benefits for these diseases. M-30 and EGCG decreased apoptosis of human SH-SY5Y neuroblastoma cells in a neurorescue, serum deprivation model, via multiple protection mechanisms including: reduction of the pro-apoptotic proteins, Bad and Bax, reduction of apoptosis-associated Ser139 phosphorylated H2A.X and inhibition of the cleavage and activation of caspase-3. M-30 and EGCG also promoted morphological changes, resulting in axonal growth-associated protein-43 (GAP-43) implicating neuronal differentiation. Both compounds significantly reduced the levels of cellular holo-amyloid precursor protein (APP) in SH-SY5Y cells. The ability of theses novel iron chelators and EGCG to regulate APP are in line with the presence of an iron-responsive element (IRE) in the 5'-untranslated region (5'UTR) of APP. Also, EGCG reduced the levels of toxic amyloid-beta peptides in CHO cells over-expressing the APP "Swedish" mutation. The diverse molecular mechanisms and cell signaling pathways participating in the neuroprotective/neurorescue and APP regulation/processing actions of M-30 and EGCG, make these multifunctional compounds potential neuroprotective drugs for the treatment of neurodegenerative diseases, such as PD, AD, Huntington's disease and amyotrophic lateral sclerosis.
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PMID:Neurorescue activity, APP regulation and amyloid-beta peptide reduction by novel multi-functional brain permeable iron- chelating- antioxidants, M-30 and green tea polyphenol, EGCG. 1790 43

Heme oxygenase-1 (HO-1) has been suggested as an important mediator of the cholesterol-independent cytoprotection actions of statins, which may be of benefit for the treatment of degenerative neurological diseases and for reduction of infarct volume after cerebral ischemia. Overexpression of HO-1, however, has dual effects under oxidative stress, and the release of ferric iron from heme under these conditions may result in detrimental rather than cytoprotective effects. This study was designed to investigate the effect of simvastatin-induced HO-1 on Neuro 2A cells in response to glucose deprivation. We demonstrated that simvastatin induced a dose- and time-dependent upregulation of HO-1 protein expression in Neuro 2A cells. The induction of HO-1 after simvastatin treatment was mediated by nuclear factor erythroid 2-related factor 2 (Nrf2), which was expressed by Western blots of nuclear fractions and retarded complex formation in the electrophoretic mobility shift assay reaction. In addition, simvastatin activated the extracellular signal-regulated kinase and p38, but not the phosphorylation of c-Jun N-terminal kinase and Akt. Glucose deprivation in the cells pretreated with simvastatin induced more HO-1 expression, and the transcript could be decreased by small interfering RNA for Nrf2. This upregulation of HO-1 was significantly associated with increased apoptosis, manifested as expression at the protein level of 17-kDa cleaved caspase-3 and increased percentage of apoptotic cells shown by flow cytometry. The increased cleaved caspase-3 expression and percentage of apoptotic cells was significantly reduced by the HO inhibitor zinc protoporphyrin. Addition of the iron chelator desferrioxamine also resulted in blockade of the aggravated apoptosis, which implies that iron production from HO-1 activity may play an important role in the increased apoptosis in response to glucose deprivation in neuronal cells pretreated with simvastatin.
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PMID:Simvastatin-induced heme oxygenase-1 increases apoptosis of Neuro 2A cells in response to glucose deprivation. 1792 92

Elevated iron accumulation has been reported in brain regions in some neurodegenerative disorders. However, the mechanism for this is largely unknown. Divalent metal transporter 1 (DMT1) is an important divalent cation transporter. The aim of the present study is to construct recombinant adenovirus encoding human DMT1 with iron responsive element (DMT1+IRE) and infect MES23.5 dopaminergic cells in order to investigate the relationship between increased DMT1+IRE expression and iron accumulation. The human DMT1 gene was obtained by RT-PCR from tissues of human duodenum. AdDMT1+IRE was successfully constructed and identified by PCR, restriction endonuclease analyses and DNA sequencing, respectively. It was able to efficiently infect MES23.5 cells, which was confirmed by RT-PCR and Western blots. When incubated with 100 microM ferrous iron for 6h, the intracellular iron levels dramatically increased in AdDMT1+IRE infected MES23.5 cells compared to the solely adenovirus infected cells. Meanwhile, the levels of hydroxyl free radicals and malondialdehyde (MDA) in these cells increased. This led to the activation of caspase-3. The apoptosis in AdDMT1+IRE infected cells was shown with hypercondensed nuclei using Hoechst staining. Analysis of DNA extracted from these cells showed the typical "ladder pattern", indicating the formation of mono- and oligonucleosomes. These results suggested that increased DMT1+IRE expression in MES23.5 cells caused the increased intracellular iron accumulation. This resulted in the increased oxidative stress leading to ultimate cell apoptosis.
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PMID:Over-expressed human divalent metal transporter 1 is involved in iron accumulation in MES23.5 cells. 1808 89

Apoptosis has been identified as one of the important mechanisms involved in the degeneration of dopaminergic neurons in Parkinson's disease (PD). Our previous study showed increased iron levels in the substantia nigra as well as loss of dopaminergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD mouse models. 1-Methyl-4-phenylpyridinium (MPP(+)) is commonly used to establish a cellular model of PD. Although intracellular iron plays a crucial role in MPP(+)-induced apoptosis, the molecular mechanism linking increased iron and MPP(+)-induced neurodegeneration is largely unknown. In the present study, we investigate the involvement of divalent metal transporter 1 (DMT1) that accounts for the ferrous iron transport in MPP(+)-treated MES23.5 cells. In the treated cells, a significant influx of ferrous iron was observed. This resulted in a decreased mitochondrial membrane potential. Additionally, an elevated level of ROS production and activation of caspase-3 were also detected, as well as the subsequent cell apoptosis. These effects could be fully abolished by iron chelator desferal (DFO). Increased DMT1 (-IRE) expression but not DMT1 (+IRE) accounted for the increased iron influx. However, there were no changes for iron regulatory protein 1 (IRP1), despite decreased expression of IRP2. Iron itself had no effect on IRP1 and IRP2 expression. Our data suggest that although DMT1 mRNA contains an iron responsive element, its expression is not totally controlled by this. MPP(+) could up-regulate the expression of DMT1 (-IRE) in an IRE/IRP-independent manner. Our findings also show that MPP(+)-induced apoptosis in MES23.5 cells involves DMT1-dependent iron influx and mitochondria dysfunction.
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PMID:Up-regulation of divalent metal transporter 1 is involved in 1-methyl-4-phenylpyridinium (MPP(+))-induced apoptosis in MES23.5 cells. 1819 77

While lysosomal disruption seems to be a late step of necrosis, a moderate lysosomal destabilization has been suggested to participate early in the apoptotic cascade. The origin of lysosomal dysfunction and its precise role in apoptosis or apoptosis-like process still needs to be clarified, especially upon carcinogen exposure. In this study, we focused on the implication of lysosomes in cell death induced by the prototype carcinogen benzo[a]pyrene (B[a]P; 50 nM) in rat hepatic epithelial F258 cells. We first demonstrated that B[a]P affected lysosomal morphology (increase in size) and pH (alkalinization), and that these changes were involved in caspase-3 activation and cell death. Subsequently, we showed that lysosomal modifications were partly dependent on mitochondrial dysfunction, and that lysosomes together with mitochondria participate in B[a]P-induced oxidative stress. Using two iron chelators (desferrioxamine and deferiprone) and siRNA targeting the lysosomal iron-binding protease lactoferrin, we further demonstrated that both lysosomal iron content and lactoferrin were required for caspase-3 activation and apoptosis-like cell death.
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PMID:A new lactoferrin- and iron-dependent lysosomal death pathway is induced by benzo[a]pyrene in hepatic epithelial cells. 1825 15

Disrupted iron metabolism and excess iron accumulation has been reported in the brains of Parkinson's disease (PD) patients. Because excessive iron can induce oxidative stress subsequently causing degradation of nigral dopaminergic neurons in PD, we determined the protective effect of a naturally occurring iron chelator, phytic acid (IP6), on 1-methyl-4-phenylpyridinium (MPP(+))-induced cell death in immortalized rat mesencephalic/dopaminergic cells. Cell death was induced with MPP(+) in normal and iron-excess conditions and cytotoxicity was measured by thiazolyl blue tetrazolium bromide (MTT assay) and trypan blue staining. Apoptotic cell death was also measured with caspase-3 activity, DNA fragmentation, and Hoechst nuclear staining. Compared to MPP(+) treatment, IP6 (30 micromol/L) increased cell viability by 19% (P<0.05) and decreased cell death by 22% (P<0.05). A threefold increase in caspase-3 activity (P<0.001) and a twofold increase in DNA fragmentation (P<0.05) with MPP(+) treatment was decreased by 55% (P<0.01) and 52% (P<0.05), respectively with IP6. Cell survival was increased by 18% (P<0.05) and 42% (P<0.001) with 30 and 100 micromol/L of IP6, respectively in iron-excess conditions. A 40% and 52% (P<0.001) protection was observed in caspase-3 activity with 30 and 100 micromol/L IP6, respectively in iron-excess condition. Similarly, a 45% reduction (P<0.001) in DNA fragmentation was found with 100 micromol/L IP6. In addition, Hoechst nuclear staining results confirmed the protective effect of IP6 against apoptosis. Similar protection was also observed with the differentiated cells. Collectively, our results demonstrate a significant neuroprotective effect of phytate in a cell culture model of PD.
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PMID:Neuroprotective effect of the natural iron chelator, phytic acid in a cell culture model of Parkinson's disease. 1825 13

After an ischemic stroke, neurons in the core are rapidly committed to die, whereas neuron death in the slowly developing penumbra is more amenable to therapeutic intervention. Microglia activation contributes to delayed inflammation, but because neurotoxic mechanisms in the penumbra are not well understood, we developed an in vitro model of microglia activation and propagated neuron killing. To recapitulate inflammatory triggers in the core, microglia were exposed to oxygen glucose-deprived neurons and astrocytes. To model the developing penumbra, the microglia were washed and allowed to interact with healthy naive neurons and astrocytes. We found that oxygen-glucose deprivation (OGD)-stressed neurons released glutamate, which activated microglia through their group II metabotropic glutamate receptors (mGluRs). Microglia activation involved nuclear factor kappaB (NF-kappaB), a transcription factor that promotes their proinflammatory functions. The activated microglia became neurotoxic, killing naive neurons through an apoptotic mechanism that was mediated by tumor necrosis factor-alpha (TNF-alpha), and involved activation of both caspase-8 and caspase-3. In contrast to some earlier models (e.g., microglia activation by lipopolysaccharide), neurotoxicity was not decreased by an inducible nitric oxide synthase (iNOS) inhibitor (S-methylisothiourea) or a peroxynitrite scavenger [5,10,15,20-tetrakis(N-methyl-4'-pyridyl)porphinato iron (III) chloride], and did not require p38 mitogen-activated protein kinase (MAPK) activation. The same microglia neurotoxic behavior was evoked without exposure to OGD-stressed neurons, by directly activating microglial group II mGluRs with (2S,2'R,3'R)-2-(2'3'-dicarboxycyclopropyl) glycine or glutamate, which stimulated production of TNF-alpha (not nitric oxide) and mediated TNF-alpha-dependent neurotoxicity through activation of NF-kappaB (not p38 MAPK). Together, these results support potential therapeutic strategies that target microglial group II mGluRs, TNFalpha overproduction, and NF-kappaB activation to reduce neuron death in the ischemic penumbra.
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PMID:Mechanisms of microglia-mediated neurotoxicity in a new model of the stroke penumbra. 1857 26

It has been found previously that vitamin B12b amplifies significantly the cytotoxic effects of ascorbic acid by catalyzing the formation of reactive oxygen species, and the antioxidant dithiothreitol (DTT), in contrast to catalase, does not prevent the cytotoxicity. Therefore, in this study we examined whether B12b is able to enhance the cytotoxicity of DTT. It was revealed that B12b strongly increases the cytotoxic effect of DTT. Vitamin B12b added to DTT catalyzed the generation and drastic accumulation of hydrogen peroxide in culture medium to a concentration of 260 microM within 7 min. The extracellular oxidative burst induced by the combination of B12b and DTT (DTT + B12b) was accompanied by intracellular oxidative stress, the destabilization of lysosomes, and damage to DNA. The accumulation of DNA lesions led to the initiation of apoptotic cell death, including the activation of caspase-3 and the release of cytochrome c. The antioxidants pyruvate and catalase completely prevented the DTT + B12b-induced oxidative stress and cell death. The iron chelators desferrioxamine and phenanthroline prevented the geno- and cytotoxic action of the combination although they did not reduce the exogenous oxidative burst, indicating a key role for intracellular iron in the cytotoxicity of the combination. Thus, vitamin B12b dramatically enhances the cytotoxicity of DTT, catalyzing the generation of hydrogen peroxide and inducing extra- and intracellular oxidative stress, early destabilization of lysosomes, and iron-dependent DNA damage.
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PMID:Vitamin B12b enhances the cytotoxicity of dithiothreitol. 1834 18


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